Cognitive decline is one of the most feared aspects of aging, and information about risk or protective factors is fervently sought. Vitamin B12 deficiency may increase risk, but the nature and magnitude of its influence is unknown -- in part, because the increase in understanding of B12 deficiency and how to detect it has outpaced epidemiologic study. Mandatory food folate fortification, whose goal is to prevent neural tube defects, is expected to have considerable unintended cognitive benefits, but such effects remain hypothetical. Furthermore, fears of cognitive harm to seniors voiced prior to the policy's implementation continue to be raised both in the US, where the addition of still more folic acid to flour is being promoted, and in countries considering fortification. Concern arose from a few historic case reports suggesting the masking of anemia and worsening of neuropsychiatric symptoms in pernicious anemia (PA) patients mistakenly treated with folic acid. Since vitamin B12 deficiency is now known to affect about 20 percent of the elderly, not just the 1-2 percent with PA or the 3-5 percent with low circulating vitamin B12 levels, any adverse effects of high folate status would have enormous public health significance. Few previous studies of cognition investigated the interaction between vitamin B12 status and folate status, and most that looked at the main- effect relations are irrelevant to fortification, since subjects rarely had folate levels consistent with the highest concentrations observed under fortification. Furthermore, validity was threatened by misclassification bias because sensitive B12-status markers, like methylmalonic acid (MMA), were not used. Finally, few studies employed comprehensive neuropsychological testing or reported results for individual domains. Thus, associations with some specific cognitive functions may have been missed. This application proposes to fill these gaps in the literature by measuring MMA in stored blood from Framingham Study participants, who were exposed to fortification and underwent folate-status assessment and extensive cognitive testing. By linking the MMA data to the cognitive data from two examination cycles, the project aims to estimate relations between vitamin B12 status and cognitive function and decline, and between high folate status and cognition in subjects stratified by vitamin B12 status. Accomplishing these aims will clarify, to an extent never before possible, the contribution of low vitamin B12 status to age-related cognitive impairment and bring real data to bear on a major, but hypothetical, criticism of folate fortification. PUBLIC HEALTH RELEVANCE: This project aims to identify risk/benefit factors for cognitive impairment and decline during aging. Its enormous public health significance derives not only from its focus on the large and growing segment of the population with low vitamin B12 status, but also from its attention to a health problem that is both serious and dreaded. Specifically, age-related cognitive decline affects everyday functioning,1 frequently evolves into a devastating clinical entity,1 and is the most feared aspect of aging.2 The project also aims to evaluate the major concern over fortification of the food supply with folic acid;namely, that neuropsychiatric problems of vitamin B12 deficient seniors will increase.3 This focus on the risks and benefits of food folate fortification makes it relevant to both national and international public health policy, as the U.S. considers whether or not to add still more folic acid to flour,4 and countries whose food supplies are not fortified eagerly await reports on America's experience before deciding whether and how to implement fortification policy. The project's focus on vitamin B12 deficiency in seniors adds to its public health significance because estimates of the prevalence of this condition have recently increased greatly from the 1-2 percent of seniors estimated to have pernicious anemia.5 About 3-5 percent of seniors have low circulating vitamin B12 levels;6 however, about 20 percent of seniors are found to be deficient when those with elevated methylmalonic acid levels are included.